PENEMS (CARBAPENEMS)

PENEMS (CARBAPENEMS)

New class of drugs which are structurallv similar to the penicillins.  

They are derived from Streptomyces species, that differ from penicillin by substitution of a CH2 group for the sulphur in the five membered ring attached to the beta lactam ring. 

Currently have the widest  activity  of any antibiotics, being highly active against a wide variety of gram positive and gram negative bacteria and are resistant to many beta–lactamases.

Carbepenems are a new class of drugs which are structurally similar to the penicillins.

These drugs were developed to deal with beta‑lactamase producing Gram-negative organisms, which were resistant to broad spectrum and extended spectrum penicillins.

Carbapenems are derived from Streptomyces species and one example is the semisynthetic imipenem which acts in the same way as the other beta-lactams.

The most extensively studied drug is imipenem.

Imipenem is N-formimidoyl derivative of Theinamycin (B-lactam antibiotic) – derived from S. cattleya.

Mechanism of action

Binds to penicillin binding proteins. Hence it disrupts cell wall synethesis and is bactericidal.

Major target is PBP-2, which they attack through a separate porin (which makes them resistant to efflux pumps). 

PBP-2 exists in low copy numbers which means that it is a much more selective target and requires action at fewer receptors to trigger lysis.

Antimicrobial spectrum

Differs from the penicillins in its antimicrobial spectrum.

 It is a broad-spectrum antibiotic with excellent activity against a variety of gram positive and gram negative  organism (both aerobic and anaerobic), by comparison to third and fourth generation cepahalosporins. 

Resistant to most forms of beta-lactamase including that  produced by staphylococcus. 

However, methicillin-resistant staphylococcus is usually resistant to imipenem.

Susceptible organisms include: Streptococci, Enterococci. Staphylococci, Listeria, Enterobacteriaceae, Pseudomonas, Bacteroides, and Clostridium. 

The high activity is attributed to stability against most of the β-lactamases  and it's ability to penetrate porin channels that usually exclude other drugs 

The carbapenems are more rapidly bactericidal than the cephalosporins and less likely to induce release of endotoxin in an animal from gram-negative sepsis. 

Resistance to carbapenems has been extremely rare in veterinary medicine.

Carbapenems are not absorbed after oral administration except a newer penem faropenem.

They are widely distributed to ECF throughout the body and reach therapeutic concentration in most tissues .

Imipenem is almost exclusively eliminated through kidneys, being  metabolized in renal tubules  by dihydropepetidase / dipeptidase  enzyme. 

Imipenem is rapidly hydrolyzed by the enzyme, dihydropeptidase, which is found in the brush border of the proximal renal tubule. 

It is always administered with cilastatin, (an inhibitor of dihydropeptidase) to decrease renal tubular  metabolism. 

This increases the elimination half life and allows the drug to be excreted in large amounts in active form into urine.

Cilastatin does not affect the antibacterial activity.

Meropenem, by contrast is stable to dihydropeptidase 

The disadvantages of carbapenems include induction of resistance, inconvenient administration, and high cost.

Carbapenems are synergistic with aminoglycosides against P.aeruginosa.

Carbapenems are used successfully in human patients for intra-abdominal infections, severe lower respiratory tract infections, septicemia and life threatening soft tissue infections and osteomyelitis.

Meropenem is as effective as cefotaxime or ceftriaxone in treatment of bacterial meningitis.

Side effects

Individuals who are allergic to the penicillins may demonstrate cross-reactivity with imipenem.  

Imipenem may produce gastrointestinal disturbances: nausea and vomiting

Seizures have been reported with high doses. Hypersalivation and vocalization, indicating pain after IM amd SC administration in dogs was noticed. 

The empirical dose in dogs  and cats is 5-10mg/kg, IV or deep IM, every 8 hours, and  in  horse : 10-20mg/kg, IV, every 6 hours .  

Meropenem, approximately equal to, or greater than imipenem. 

Its advantage over  imipenem is that it is more soluble and can be administered in less fluid volume and more rapidly.  For example, small volumes can be administered subcutaneously with almost complete absorption. 

There also is a lower incidence of adverse effects to the central nervous system, such as seizures 

The recommended  empirical dose in dog is  2-5mg/kg, slow IV (with  IV fluids), every 6 hours; 5 -10mg/kg,  deep IM every 8 hours  or 8-12 mg/kg SC,   every 8 -12 hours.